What is Benign Prostatic Hyperplasia (BPH)?
BPH is a noncancerous growth of the prostate gland. The prostate surrounds the urethra at the base of the bladder. BPH is sometimes called prostate enlargement. At age 20, the prostate is roughly the size of a walnut. By age 70, the average prostate has doubled in size. BPH occurs to some degree in 80 percent of men, but only one-third of men develop significant lower urinary tract symptoms (LUTS) that may require treatment. An estimated 6.3 million men are bothered by BPH. The disease accounts for 6.4 million doctor visits and more than 400,000 hospitalizations each year.

What Causes BPH and LUTS?
The fundamental cause of BPH is unknown. Because BPH occurs mainly in older men, some researchers believe that factors related to aging may spur the development of BPH. Also, men who do not produce the male hormone dihydrotestosterone (DHT) do not develop BPH. Some men may also have a genetic or familial predisposition for BPH.

Regardless, as the prostate gets larger, it increasingly obstructs the flow of urine, results in changes in bladder function and, in turn, LUTS. Age-related changes such as increased urine production, deterioration in bladder function and sleep disturbances that lead to frequent awakening at night can also cause LUTS.

What Are the Symptoms of BPH?
In late middle age, most men begin experiencing bothersome lower urinary tract symptoms (LUTS) that may interfere with daily activities and decrease quality of life:

• more frequent urination, especially at night
• the sensation of incomplete bladder emptying, and
• hesitant, interrupted, weak urinary stream.

LUTS is not unique to BPH but it is most common in men with the disease. LUTS is usually measured with the American Urological Association (AUA) Symptom Score Index, developed more than a decade ago. The questionnaire is known outside the United States as the International Prostate Symptom Score. Scores range from 0 to 35, from least to most severe. A score below 8 reflects mild symptoms that seldom affect quality of life. Men seeking therapy for BPH typically have scores between 15 and 18.

What Are the Complications of BPH?
Men with BPH can lose bladder control and develop acute urinary retention (AUR), a painful inability to urinate that requires catheterization to release urine from the bladder. Although AUR can occur in men who do not have enlarged prostates, men with larger prostates are at greater risk for this complication. Urinary retention may be triggered by taking over-the-counter cold or allergy medicines, alcohol, cold temperatures, or a long period of immobility. Men rarely develop recurrent urinary tract infection or altered kidney function from BPH, but these potential complications are serious.

What Invasive Treatments Are Used for BPH?
When symptoms are not relieved by medical therapy or a man develops AUR, he may need an invasive treatment such as transurethral microwave thermotherapy or surgery to reduce the size of the prostate and increase the flow of urine. The most common surgery for BPH is transurethral resection of the prostate (TURP).

Finasteride (Proscar) and dutasteride (Avodart) are two 5a-reductase inhibitors approved for BPH. Finasteride, the oldest of these drugs, and the one used in MTOPS, lowers the level of DHT in the prostate and shrinks the prostate by about 20 percent, increasing urinary flow and reducing symptoms. Previous studies have also documented that finasteride reduces the risk of AUR and the need for BPH-related surgery. Common side effects of finasteride are erectile dysfunction, decreased libido, and abnormal ejaculation, which occur in 3 to 10 percent of men taking the drug.

What Was the Purpose of MTOPS?
Physicians have known for some time that medical therapy can partially relieve BPH symptoms. In general, alpha blockers are thought to relieve symptoms more effectively than finasteride. However, one study ( New England Journal of Medicine , 338:557-563, 1998) showed that finasteride reduced the risk of urinary retention and the need for BPH-related surgery. MTOPS addressed the major question of whether the combination of an alpha blocker (doxazosin) and finasteride would be more effective than either drug alone in preventing the clinical progression of BPH. This question had not been addressed in other studies.

What is Clinical Progression of BPH?
In MTOPS, one or more events signaled “worsening” or clinical progression of BPH: worsening symptoms or developing acute urinary retention, recurrent urinary tract infections, or deterioration in kidney function due to obstruction. Worsening symptoms was defined as at least a 4-point increase in AUA Symptom Score from an individual's starting point, which is enough to decrease a man's sense of well-being, according to prior studies.

How Does MTOPS Differ From Prior Medical Therapy Trials?
MTOPS treated men an average 4.5 years, longer than most published drug treatment trials for BPH, and provided important data about the value of combination therapy for preventing progression of BPH. Although a 4-year trial for finasteride had been published ( New England Journal of Medicine , 338:557-563, 1998), most drug trials for BPH are typically about a year long, and no studies longer than a year have been published about alpha blockers for BPH. In addition, the value of combination therapy was seriously questioned following the conclusion of a year-long Veterans Administration (VA) trial that using the alpha blocker terazosin and finasteride together did not relieve symptoms and improve urinary flow rate any better than terazosin alone ( New England Journal of Medicine, 335:533-539, 1996). Also, the VA and MTOPS studies were designed differently--VA looked at symptom and flow rate improvements and MTOPS looked at clinical progression of BPH.

What Was the Primary Finding of the MTOPS Study?
The combination of doxazosin and finasteride significantly delayed the clinical progression of symptomatic BPH compared to single-drug therapy and placebo. Finasteride alone and the combination therapy reduced the long-term risk of acute urinary retention and BPH-related invasive therapy. Combination therapy was significantly more effective than either drug alone for reducing symptoms and improving urinary flow rate. Common adverse events were similar to previously reported trials.

Should All Men With BPH Symptoms Be On Combination Therapy?
Guidelines from the American Urological Association, the Agency for Healthcare Research and Quality and the International Consultation on BPH recommend that men talk to their doctors about the benefits and risks of available treatments. The benefits, including reducing symptoms and delaying clinical progression (the latter clearly demonstrated for the first time by MTOPS), must be balanced against the risk of side effects and the additional expense of combination therapy.

MTOPS has shown that men who had higher baseline serum prostate specific antigen levels and larger prostates were more likely to experience progression of BPH and most likely to benefit from combination therapy--those with prostates larger than 40 ml (30 percent of participants) and serum PSAs above 4 ng/milliliter (20 percent of participants). Risk of BPH progression increased with rising PSA and prostate size in men on placebo or doxazosin, but not in men on finasteride or the combination.

Were There Other Important Findings from the MTOPS Trial?
The combination treatment and finasteride alone also significantly reduced the risk of invasive therapy , by 67 percent and 64 percent, respectively; doxazosin reduced the risk by 3 percent. Most men who had invasive therapy for BPH had the gold-standard surgical procedure, transurethral resection of the prostate (TURP).

Did Medical Therapy Prevent Prostate Cancer in the MTOPS Trial?
MTOPS was not designed to test whether medical therapy would prevent prostate cancer. However, the National Cancer Institute's Prostate Cancer Prevention Trial of 18,000 men has found that finasteride reduced the risk of prostate cancer by 25 percent. Detailed information about the Prostate Cancer Prevention Trial and prostate cancer in general is available from the National Cancer Institute at http://www.nci.nih.gov/pcpt. PCPT results were published in the New England Journal of Medicine on July 17, 2003 (NEJM 2003;349:213-22).