Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate. It is the most common cause of bladder outlet obstruction in the male geriatric population and is highly prevalent in men over 40 of all races and cultures. Occasionally, BPH can lead to complications including urinary retention, renal insufficiency, urinary tract infections, hematuria and bladder stones, but the vast majority of patients present with symptomatic complaints including urinary frequency, nocturia, urgency, hesitancy, weak stream, intermittent stream or the sensation of incomplete bladder emptying. This chapter will discuss the prevalence of prostatism, pathophysiology of BPH and outlet obstruction, initial evaluation of the patient, and both medical and surgical treatment options.

Benign prostatic hyperplasia is the most common nonmalignant neoplasm in older men. Microscopic evidence of BPH is found in 50 percent of men by the age of 60 and 90 percent of men by the age of 85. It is estimated that one in every four males will seek treatment for BPH by the age 80. In the 1980s, transurethral resection of the prostate (TURP) was the second most common surgical procedure in men over 65, second only to cataract surgery. Since then, there has been a fifty percent decline, likely due to improvements in medical therapy and greater patient involvement in the decision making process. In a population based survey of men over 60 with no history of prostate surgery the prevalence of one or more symptoms of prostatism (hesitancy, straining, weak stream, intermittency or use of a catheter) was 35 percent. The annual incidence rates during one and two years of follow up were 16.4 percent and 16.1 percent respectively.

BPH is due to excessive cellular growth of both the glandular and stromal components of the prostate gland. This growth is androgen sensitive and does not develop in men who have been castrated; castration has also been shown to promote regression. This excessive growth originates in the transition zone of the prostate which surrounds the urethra leading to compression of the urethral lumen and symptoms of obstruction.

The presumptive diagnosis of BPH can be made when a male patient over the age of 50 presents with one or more symptoms of prostatism. The Agency for Health Care Policy and Research has published guidelines for evaluation and management of patients with BPH. It is recommended that all patients presenting with symptoms of prostatism have a complete medical history with special attention focused on the urinary tract, a complete physical exam including a digital rectal exam, urinalysis and serum creatinine. Measurement of prostate-specific antigen (PSA) is considered optional. Tests that may be helpful include uroflowmetry – this may identify patients with low urine flow rates who may benefit more from therapy and is a way to follow therapy. Post-void residual (PVR), preferably measured by ultrasound, can be used to identify patients with higher PVR who may also be more likely to benefit from therapy. Pressure-flow studies may be useful in distinguishing patients who may have a component of bladder dysfunction.

American Urological Association (AUA) Symptom Index for BPH is a self- or physician-administered questionnaire which correlates highly with a subject’s global ratings of the magnitude of their urinary problem (Appendix A). Symptoms are classified as mild (0 - 7), moderate (8 - 19) and severe (20 - 35). The index should be used in treatment planning and in periodic reassessment.

Treatment

A treatment plan should be guided by the severity of symptoms and patient preferences. For patients who have mild symptoms by the AUA index, watchful waiting is appropriate. ⁴ It is not possible to predict which of these patients will have progression of symptoms or complications of the disease. In a survey of patients with mild symptoms, 37.5 percent reported no symptoms one year later, and only 12.5 percent progressed to severe symptoms.² These patients should be reassessed on a regular basis with symptom index, physical exam and routine laboratory tests (UA, creatinine). Patients with moderate to severe symptoms should be educated about the different treatment options and an informed decision be made according to the patient’s preferences. Treatment options include watchful waiting, medical therapy and surgery. Any patient with a complication of BPH (refractory retention, recurrent UTIs, recurrent or persistent hematuria, bladder stones, renal insufficiency) should be referred for surgery. ⁴

Alpha-1-adrenergic receptor blockers (terazosin, doxazosin, tamsulosin) block the adrenergic receptors in hyperplastic prostatic tissue, the prostatic capsule and the bladder neck. This results in decreased smooth muscle tone and a decrease in resistance to urinary flow through the bladder neck and prostatic urethra. The alpha-adrenergic antagonist that has been most studied is terazosin. In a randomized, double-blind, placebo-controlled, multicenter study of 285 men with symptomatic BPH randomly assigned to receive placebo, or 2, 5, or 10mg of terazosin administered once daily for 12 weeks, the men in the 5 and 10 mg terazosin groups had a significantly greater decrease in symptom score compared to those who received placebo. The percentage reduction in symptom index for placebo, and 2, 5 and 10mg treatment groups were 23 percent, 32 percent, 32 percent and 44 percent respectively. The group receiving 10mg of terazosin also had a statistically significant increase in urinary peak flow over the placebo group. In a second study of 160 men over 45 years of age and with symptoms of BPH, the terazosin treated group had a 42 percent decrease in symptoms score and a 30 percent increase in urinary peak flow compared to 11 percent and 14 percent respectively for the placebo group. The time to maximal benefit was four to six weeks. The side effects of terazosin in each of these studies included dizziness (10 - 19 percent) and postural hypotension (8.3 percent) with one patient in the 10 mg treatment group suffering a syncopal episode. These results suggest that terazosin given once daily in doses up to 10 mg is effective in alleviating the symptoms of BPH. We recommend starting with a low dose (1mg daily) and titrating up over two to three weeks to a maximum of 10 mg/day.

Very few head to head trials of the alpha-1-adrenergic receptor blockers exist but a meta-analysis by Djavan and Marberger involving data from 6333 patients in placebo controlled trials and 507 patients in head to head trials concluded that all alpha-1-adrenergic receptor blockers had equally efficacy but tamsulosin (Flomax™) had a lower incidence of side effects. In trials of tamsulosin 4-10 percent of patients withdrew secondary to bothersome side effects, this was equal to the rate with placebo. However with terazosin (Hytrin™) and doxazosin (Cardura™) an additional 4-10 percent above that of the placebo rate withdrew. Medical Letter consultants agree with that tamsulosin appears to be as effective as terazosin or doxazosin and that the reported incidence of side effects is lower however they do emphasize that direct comparisons are lacking.

5 alpha-reductase inhibitors: Within the prostate, 5 alpha-reductase enzymatically converts testosterone to dihydrotestosterone. Blockage of this enzyme results in androgen deprivation within the prostate. Finasteride (Propecia™) is a potent inhibitor of 5 alpha-reductase. In a randomized, double-blind, multicenter, placebo controlled study, 895 men with symptoms of BPH and an enlarged prostate by digital rectal exam were treated with finasteride (1 or 5 mg/day) or placebo. Compared to the men in the placebo group, the men treated with finasteride 5mg/day had a significant decrease in the total urinary-symptom scores (21 percent vs. 2 percent), an increase of 1.6 ml/sec in maximal urinary-flow rate, and a 19 percent decrease in prostatic volume. The changes in symptoms score reached statistical significance after two months of therapy. These results have been replicated in other studies. Five percent of patients noted side effects including decreased libido, ejaculatory dysfunction and impotence.

Herbal Remedies: Although no herbal medications are approved for the treatment of BPH in the United States, many men self-medicate with these agents and it is important to know something about them. The most common remedies include saw palmetto (active extract - Serenoa repens/permixon), beta-sitoserol and cernilton an extract from rye grass pollen. A meta-analysis of permixon which included 2859 patients in both randomized and open label clinical trials showed a significant improvement in peak urinary flow rate and a decrease in episodes of nocturia. The Cochrane Database Review of beta-sitosterols concluded that there is evidence that suggests they improve urinary flow measures and symptoms but that long term trials are lacking. They also reviewed cernilton and concluded that the clinical trials were lacking in quality but there is a suggestion that cernilton improves urinary symptoms. However due to a lack of quality control in the industry and the absence of long term trials it would be difficult to recommend any of these therapies to a patient.

Comparison of medical therapies: There has been a trial comparing placebo, terazosin (10mg/day), finasteride (5mg/day) and the combination of both drugs in 1229 men 45 to 80 years of age with symptomatic BPH. AUA symptom index scores and urinary flow rates were evaluated at baseline and follow up for one year. The mean changes from base line symptom scores in the placebo, finasteride, terazosin and combination therapy group were 2.6, 3.2, 6.1 and 6.2 points respectively. Urinary flow rates increased 1.4, 1.6, 2.7 and 3.2 ml/sec respectively. The conclusion of the authors of this study was that in men with BPH, terazosin was effective whereas finasteride was not and the combination of the two was no more effective than terazosin alone. One important note to make on the difference between this study and the previous studies on finasteride is that in this study an enlarged prostate was not a criterion for entrance into the study and the average prostatic volume was 37 ml whereas in all of the previous studies on finasteride, prostatic enlargement was an entry criteria and the average prostate size ranged from 47 to 60 ml. In conclusion, it appears that terazosin is more effective and has a more rapid onset of action than finasteride and should therefore be used as a first line agent. In men with an enlarged prostate, finasteride may be a reasonable option.

Transurethral resection of the prostate (TURP) is the most common surgical treatment for BPH, and prior to the recent developments in medical and newer surgical therapies it was the mainstay of treatment. A multicenter, randomized trial was conducted comparing TURP with watchful waiting in 556 men with moderate symptoms of BPH with a primary endpoint of treatment failure, defined as death, repeated or intractable urinary retention, a residual urinary volume of >350 ml, the development of bladder calculus, new and persistent incontinence, a high symptom score, or a doubling of the serum creatinine. After an average follow-up of 2.8 years, TURP was superior to watchful waiting in preventing treatment failure (23 vs. 47 patients respectively) and in improving symptom scores (mean score at follow-up, 4.9 vs. 9.1, change from baseline, -9.6 vs. -5.5). Surgery in this study was not associated with impotence or urinary incontinence, however in other studies erectile dysfunction that was not present preoperatively occurred in 10 to 15 percent of patients and retrograde ejaculation occurred in at least one third of patients. ⁹

In a retrospective review of 3,885 patients who underwent TURP, the postoperative mortality rate was 0.2 percent and the immediate postoperative morbidity rate included failure to void (6.5 percent), bleeding requiring transfusion (3.9 percent), genitourinary infections (2.3 percent) and discharge from hospital with indwelling catheter (2.4 percent). A later follow up to this study showed that although the men going for TURP are now significantly older than before, the post operative mortality rate remained low at 0.4 percent for thirty days. In conclusion, surgery appears to offer the best chance for symptom improvement but it also has the highest complication rates. Other minimally invasive surgical treatments have developed in recent years. The best studied of these is transurethral incision of the prostate (TUIP). It appears to have the same efficacy as TURP with fewer side effects, but it is limited to men with prostates of 30 grams or less. ⁴ Prostatic stents, microwave therapy and laser prostatectomy are all newer therapies but remain unproven. Open prostatectomy is also a possibility for men with extremely large prostates. Balloon dilatation of the prostatic urethra is less effective than surgery but can provide temporary relief of symptoms (<2 years) with few complications. Surgery does not have to be a treatment of last resort. Some patients may prefer to undergo a surgical procedure to chronic medical therapy. Surgery is also the treatment of choice for any patients with complications of BPH.