Benign prostatic hyperplasia (BPH), a nearly ubiquitous condition, is the most common benign neoplasm of American men. Three types of prostate gland tissue: epithelial or glandular, stromal or smooth muscle, and capsule. Both stromal tissue and capsule are embedded with α1-adrenergic receptors.
The precise pathophysiologic mechanisms that cause BPH are not clear. Both intraprostatic dihydrotestosterone (DHT) and type II 5α-reductase are thought to be involved.
BPH commonly results from both static (gradual enlargement of the prostate) and dynamic (agents or situations that increase α-adrenergic tone and constrict the gland’s smooth muscle) factors. Examples of drugs that can exacerbate symptoms include testosterone, α-adrenergic agonists (eg, decongestants), and those with significant anticholinergic effects (eg, antihistamines, phenothiazines, tricyclic anti- depressants, antispasmodics, and antiparkinsonian agents).
Patients present with a variety of signs and symptoms categorized as obstructive or irritative. Symptoms vary over time. Obstructive signs and symptoms result when dynamic and/or static factors reduce bladder emptying. Patients experience urinary hesitancy, urine dribbles out of the penis, and the bladder feels full even after voiding.
Irritative signs and symptoms are common and result from long-standing obstruction at the bladder neck. Patients experience urinary frequency, urgency, and nocturia. BPH progression may produce complications including chronic kidney disease, gross hematuria, urinary incontinence, recurrent urinary tract infection, bladder diverticula, and bladder stones.
Includes careful medical history, physical examination, objective measures of bladder emptying (eg, peak and average urinary flow rate and postvoid residual [PVR] urine volume), and laboratory tests (eg, urinalysis and prostate-specific antigen [PSA]). On digital rectal examination, the prostate is usually but not always enlarged (above 20 g), soft, smooth, and symmetric.
Management options include watchful waiting, drug therapy, and surgical intervention. The choice depends on severity of signs and symptoms. Watchful waiting is appropriate for patients with mild disease. Patients are reassessed at 6 to 12 month intervals and educated about behavior modification, such as fluid restriction before bedtime, avoiding caffeine and alcohol, frequent emptying of the bladder, and avoiding drugs that exacerbate symptoms.
Pharmacologic therapy is appropriate for patients with moderate BPH symptoms and as an interim measure for patients with severe BPH. Pharmacologic therapy interferes with the stimulatory effect of testosterone on prostate gland enlargement (reduces the static factor), relaxes prostatic smooth muscle (reduces the dynamic factor), or relaxes bladder detrusor muscle.
Initiate therapy with an α1-adrenergic antagonist for faster onset of symptom relief. Select a 5α-reductase inhibitor in patients with a prostate gland more than 40 g. Consider combination therapy for symptomatic patients with a prostate gland more than 40 g and PSA of 1.4 ng/mL or more (1.4 mcg/L). Consider monotherapy with a phosphodiesterase inhibitor or use in combination with an α-adrenergic antagonist when erectile dysfunction and BPH are present.
Agents that interfere with androgen stimulation of the prostate are not popular in the United States because of adverse effects. Luteinizing hormone–releasing hormone agonist leuprolide and goserelin decrease libido and can cause erectile dysfunction, gynecomastia, and hot flashes. Antiandrogens bicalutamide and flutamide cause nausea, diarrhea, and hepatotoxicity.
α-Adrenergic antagonists relax smooth muscle in the prostate and bladder neck, increasing urinary flow rates by 2 to 3 mL/sec in 60% to 70% of patients and reducing PVR urine volumes. α1-Adrenergic antagonists do not decrease prostate volume or PSA levels.
Prazosin, terazosin, doxazosin, and alfuzosin are second-generation α1-adrenergic antagonists. They antagonize peripheral vascular α1-adrenergic receptors in addition to those in the prostate. Adverse effects include first-dose syncope, orthostatic hypotension, and dizziness. Alfuzosin is less likely to cause cardiovascular adverse effects than other second-generation agents.
Slowly titrate to a maintenance dose at bedtime to minimize orthostatic hypotension and first-dose syncope with immediate-release formulations of terazosin and doxazosin. Sample titration schedules for terazosin include:
Tamsulosin and silodosin, third-generation α1-adrenergic antagonists, are selective for prostatic α1A-receptors. Therefore, they do not cause peripheral vascular smooth muscle relaxation and associated hypotension. Tamsulosin is a good choice for patients who cannot tolerate hypotension; has severe coronary artery disease, volume depletion, cardiac arrhythmias, severe orthostasis, or liver failure; or are taking multiple antihypertensives. Tamsulosin is also suitable for patients who want to avoid the delay of dose titration.
Potential drug interactions include decreased metabolism of α1-adrenergic antagonists with CYP 3A4 inhibitors (eg, cimetidine and diltiazem) and increased catabolism of α1-adrenergic antagonists with concurrent use of CYP 3A4 stimulators (eg, carbamazepine and phenytoin). Reduce the dose of silodosin in patients with moderate renal impairment or hepatic dysfunction.
5α-Reductase inhibitors interfere with the stimulatory effect of testosterone. These agents slow disease progression and decrease the risk of complications. Compared with α1-adrenergic antagonists, disadvantages of 5α-reductase inhibitors include 6 months of use to maximally shrink prostate, less likely to induce objective improvement and more sexual dysfunction.
Whether the pharmacodynamic advantages of dutasteride confer clinical advantages over finasteride is unknown. Dutasteride inhibits types I and II 5α-reductase, whereas finasteride inhibits only type II. Dutasteride more quickly and completely suppresses intraprostatic DHT (vs 80%–90% for finasteride) and decreases serum DHT by 90% (vs 70%).
5α-Reductase inhibitors may be preferred in patients with uncontrolled arrhythmias, poorly controlled angina, use multiple antihypertensives, or cannot tolerate hypotensive effects of α1-adrenergic antagonists. Measure PSA at baseline and again after 6 months of therapy. If PSA does not decrease by 50% after 6 months of therapy in a compliant patient, evaluate the patient for prostate cancer.
5α-Reductase inhibitors are in FDA pregnancy category X and are therefore contraindicated in pregnant women. Pregnant and potentially pregnant women should not handle the tablets or have contact with semen from men taking 5α-reductase inhibitors.
Increase in cyclic GMP by phosphodiesterase inhibitors (PI) may relax smooth muscle in prostate and bladder neck. Effectiveness may be result of direct relaxation of detrusor muscle of bladder.
Tadalafil 5 mg daily improves voiding symptoms but does not increase urinary flow rate or reduce PVR urine volume. Combination therapy with α-adrenergic antagonist results in significant improvement in lower urinary tract symptoms, increased urinary flow rates, and decreased PVR volume.
Addition of oxybutynin and tolterodine to α-adrenergic antagonists relieves irritative voiding symptoms including urinary frequency, urgency, and nocturia. Start with lowest effective dose to determine tolerance of CNS adverse effects and dry mouth. Measure PVR urine volume before initiating treatment (should be less than 250 mL).
If systemic anticholinergic adverse effects are poorly tolerated, consider transdermal or extended-release formulations or uroselective agents (eg, darifenacin or solifenacin).
Prostatectomy, performed transurethrally or suprapubically, is the gold standard for treatment of patients with moderate or severe symptoms of BPH and for all patients with complications. Retrograde ejaculation complicates up to 75% of transurethral prostatectomy procedures. Other complications seen in 2% to 15% of patients are bleeding, urinary incontinence, and erectile dysfunction.