Michael J. Naslund, M.D.
Benign prostatic hyperplasia (BPH) is a common disease process which affects the majority of men as they age. Men commonly develop urinary symptoms in their late 40's or early 50's because of an enlarged prostate. In a subset of men, these symptoms are progressive, they become bothersome and require treatment. In other men, the symptoms do not create great bother and are manageable with watchful waiting. The goals of this article are to discuss the pathogenesis and natural history of prostate enlargement, discuss the medical, minimally invasive and surgical treatment options available, and compare the treatment outcomes and complications which can occur with different therapeutic approaches.
The exact molecular mechanism(s) that causes prostate enlargement is not known. It is known that advancing age and male hormones play a major role in the gradual and continuous enlargement of the prostate gland which most men experience. Prostatic hyperplasia can be seen microscopically in men in their 30’s and 40’s but significant prostate enlargement generally begins in the late 40’s or older. By the time a man has reached his 70’s or 80’s, there is approximately a 90% chance that he will have an enlarged prostate (EP).
In addition to aging, male hormones are required for prostate enlargement to occur. Testosterone, produced by the testes, is converted to dihydrotestosterone (DHT) which is the major androgen that causes the prostate to enlarge as men age. It is hypothesized that multiple growth factors and perhaps changes in the characteristics of hormone receptors are involved in prostate enlargement but the precise mechanism of this process remains unclear.
As the prostate gland enlarges, it causes partial, and at times complete, obstruction of urinary flow from the bladder. Since the bladder is a muscle, the bladder wall becomes thicker and stronger when it has to squeeze harder to empty through the obstruction of the prostate (Figure 1). The thick wall bladder does not stretch as readily as a thinner softer bladder so the functional urine capacity of the bladder decreases. In addition, in many men the bladder becomes hypersensory so that a smaller volume of urine and a lower pressure of urine in the bladder feels like a full bladder. The result of this process is a constellation of urinary symptoms which are commonly called lower urinary tract symptoms (LUTS).
LUTS are divided into two broad categories, obstructive and irritative symptoms (Table I). The most common symptoms that bother men are irritative symptoms such as nocturia and frequency. These symptoms occur because the functional capacity of the bladder is decreased and it is hypersensory which makes men have to empty their bladder with lower volume than when they were younger. Urgency (the sudden urge to urinate which is hard to control) occurs because the bladder has an uninhibited muscle contraction as a result of it’s hypersensory state. The obstructive symptoms (weak stream, hesitancy, double voiding, intermittent stream, post void dribbling) occur from the same mechanism one would expect from pumping water through a partially plugged pipe: the obstruction diminishes the flow and requires a higher pressure to initiate bladder emptying.
The symptom nocturia deserves special mention. This is probably the most bothersome symptom to the majority of men and certainly the most bothersome symptomto the wives’ of those men. It is important to know that nocturia can occur from causes other than EP. Certainly, an enlarged prostate is one of the more common, if not the most common cause of nocturia and in a large percentage of cases, treatment of the enlarged prostate improves nocturia significantly. The nocturia can also be caused by increased fluid intake in the evening, a light sleep pattern where a man awakens for other reasons and gets up to urinate because he has some urine in his bladder, and fluid retention during the day which leads to an increase in urine volume at night.
As people age, it is common for them to retain fluid during the day. This can be manifested as swelling in the feet and ankles in many people. When a person lies down, and the force of gravity comes off the kidneys and they “float”, blood flow through the kidneys increases. In patients who are fluid overloaded, there will be an increased volume of urine produced. Since most people do not lie down much during the day, the increased urine output occurs at night while they sleep causing them to have to urinate several times. A patient who has few if any complaints about urinary frequency during the day but has frequent urination during the night needs to consider the possibility that the problem is not the prostate gland but instead retention of fluid during the day. These problems are generally best treated by a primary care physician instead of by a urologist.
A large subset of men with LUTS do not have particularly enlarged prostates. In these men, the smooth muscle in the bladder neck and prostatic urethra does not relax during urination like it normally does and they end up with a “functional” obstruction. Normally, when a man urinates, the bladder squeezes and the bladder neck and prostatic urethra relax and open and the urine flows out through a good sized opening. If the bladder neck and prostatic urethra do not relax, out flow is impeded. There is smooth muscle in the bladder neck and prostate which normally relaxes. This relaxation is modulated by alpha receptors (Figure 2). As we will learn later in this article, one of the major first line treatments for LUTS is alpha blockers. These medicines help relax the bladder outlet and prostatic urethra.
The large majority of men with prostate enlargement present to their physician with a complaint of urinary symptoms. A subset of these men are at risk for progression to urinary retention (where the bladder can’t empty and a catheter is required for drainage) or prostate surgery (discussed below). As we will see, men primarily at risk for urinary symptoms can be treated differently than men who are also at risk for progression to retention or surgery.
An important recent trial on the natural history of prostate enlargement and medical management of BPH was published in the New England Journal of Medicine in December of 2003. The trial was named Medical Therapy of Prostatic Symptoms (MTOPS). This NIH sponsored study provided a wealth of new information on the natural history and medical management of BPH. A few of the more important findings were that in many men, combination medical therapy (alpha blocker plus 5-alpha reductase inhibitor) works better than either medication class alone. In addition, alpha blockers are an excellent medication choice to control bothersome urinary symptoms while 5-alpha reductase inhibitors have the advantage of decreasing the risk of a patient developing urinary retention or the need for prostate surgery. In the long run, 5-alpha reductase inhibitors also provide excellent symptom control for men with enlarged prostates.
Bothersome urinary symptoms are the most common complaint for a man with an enlarged prostate. Some men go into urinary retention from this process where they are unable to empty their bladder despite the fact that it is full. Urinary retention can be caused by obstruction of the bladder outlet from an enlarged prostate, swelling of the prostate because of a prostate infarct, the swelling of the prostate because of a prostatic infection (prostatitis), or decreased force of the bladder contraction caused by several medication classes (antihistamines, decongestants, anti-depressants, etc.). Acute urinary retention generally requires catheter drainage of the bladder. Depending on the circumstances, some men will be able to urinate spontaneously after a few days of catheter drainage. Others will be able to urinate adequately with medical management and yet others will require prostate surgery to eliminate the obstruction (see below).
A man who has bothersome urinary symptoms should see his physician for evaluation. There is a subset of men who ignore their symptoms and end up with a poorly functioning, over-distended bladder which sometimes is permanently damaged with long term obstruction. Men with long standing symptoms and prostatic obstruction are also at increased risk for recurrent urinary tract infections, bladder stones and in extreme cases, dilation and damage to the kidneys.
Watchful waiting is excellent treatment option for a large percentage of men with LUTS. Watchful waiting is appropriate in a man who has lower urinary tract symptoms which do not significantly bother him or interfere with his lifestyle and who maintains good bladder function and good bladder emptying. Most men who undergo watchful waiting should be seen by their physician on an annual basis and have an assessment of their urinary symptoms, a digital rectal exam to check the prostate for signs of cancer and a prostate specific antigen (PSA) blood test to evaluate for prostate cancer which may not be palpable on rectal exam. If a man’s symptoms worsen, he would then be offered treatment options that are discussed below. A large percentage of men can be managed for years, or their entire lives, with watchful waiting and never require aggressive treatment for their prostatic enlargement.
Medical management is first line therapy for the majority of men who require treatment for prostate enlargement. There are 2 broad classes of medications which have a proven long term track record in the management of this disease process; alpha blockers and 5-alpha reductase inhibitors.
Alpha blockers are the drug class which offer excellent and rapid relief of LUTS from prostate enlargement. Alpha blockers relax the smooth muscle in the bladder neck and prostatic urethra and effectively “dilate the pipe” to allow better flow of urine. Patients generally notice some improvement in their symptoms within 2 to 5 days and will usually enjoy significant improvement in their symptoms within a month when taking alpha blockers. Like all the treatments that we’ll be discussing, alpha blockers do not work on all patients. In some men, symptoms don’t improve, in others, side effects can be bothersome and make the medication unacceptable.
There are four alpha blockers available on the market. Terazosin and Doxazosin are generic medications. These drugs were initially designed to be anti-hypertensives but have the beneficial "side effect" of improving urinary symptoms. These drugs are cumbersome in that they require dose titration to minimize the risk of side effects. These drugs also carry a higher risk of systemic side effects such as syncope, dizziness and decreased blood pressure because they are not uroselective and act in the peripheral vasculature as well as on the prostate and bladder. Tamsulosin and Alfuzosin are newer medications which are uroselective. Uroselectivity indicates that the medication acts primarily on the bladder neck and prostate. As a result, these newer medications carry a lower risk of systemic side effects and do not require dose titration (Table 2).
The American Urological Association published BPH treatment guidelines in 2003. Included in these guidelines was an analysis of all data available in the literature on alpha blockers. The concensus of the guidelines committee was that the efficacy of all four alpha blockers is roughly equivalent in terms of urinary symptom improvement and urinary flow rate improvement. There are differences in the side effect profile of each medication. Some patients tolerate one medication better than the other. These issues are best discussed with your physician.
The dosing of the four alpha blockers is different as well. Terazosin and doxazosin are generally taken at bedtime because drowsiness is a fairly common side effect. Tamsulosin is best taken 30 minutes after a meal while Alfuzosin is best taken with a meal. The reason for these dosing recommendations is the absorption of these two medications is better if they are taken when there is food in the stomach. Men who take Tamsulosin or Alfuzosin at bedtime generally do not get maximal efficacy from these medications.
5-alpha reductase inhibitors act to directly reverse the disease process of an enlarged prostate. These medications block the conversion of testosterone to dihydrotestosterone (DHT) (Figure 3A). The resulting decrease in DHT causes an enlarged prostate to shrink. The shrinkage alleviates bladder outlet obstruction and over time will improve urinary symptoms, bladder emptying and urinary flow rate. This medication class has also been shown in the MTOPS trial and in other trials to decrease the risk of urinary retention and the need for prostatic surgery.
Finasteride blocks the type II 5-alpha reductase enzyme only. Dutasteride blocks the type I and type II 5-alpha reductase enzymes.(Figure 3B) The advantage of dual inhibition (blocking both the type I and type II 5-alpha reductase enzymes) is a greater reduction in blood levels of DHT.
5-alpha reductase inhibitors take 6 to 12 months to have an effect on urinary symptoms. The reason for this is that the prostate shrinks slowly as DHT levels decrease. The MTOPS trial (see above) demonstrated that 5-alpha reductase inhibition significantly lowers the risk of urinary retention and prostate surgery over a 4 to 5 year period when compared to patients taking placebo. Alpha blockers do not have this beneficial effect. Urinary symptoms also improve significantly in men taking 5-alpha reductase inhibitors, symptom improvement is greatest in men who have larger prostates.
5-alpha reductase inhibitors are generally well tolerated. Medication is taken once per day at any time. Approximately 7% of men have a decrease in erections, sex drive or ejaculate volume. There is also a low chance of breast enlargement or breast tenderness. If the medication is stopped, these side effects will resolve if they’re from the medication.
Men who have bothersome urinary symptoms and significant prostate enlargement are often best treated with combination medical therapy which would include an alpha blocker and a 5-alpha reductase inhibitor. The MTOPS trial demonstrated that the overall risk of progression of BPH is lowest in men on combination medical therapy. In some situations, the cost of taking 2 medications can be prohibitive. There is evidence that some patients on combination medical therapy can discontinue their alpha blocker after 6 to 12 months of treatment and maintain both their symptom improvement and a lowered risk of surgery and retention with the 5-alpha reductase inhibitor alone. This process is not successful for all patients.
Phytotherapy with compounds such as Saw Palmetto or Africanum Pygeum is widely used for treatment of urinary symptoms. The effectiveness (or lack thereof) of phytotherapy is unclear at the present time. Many studies on these compounds have been poorly controlled and the well controlled studies show variable results. To this end, the NIH is sponsoring a trial on phytotherapeutic agents (the trial is called CAMUS) to try to determine the effectiveness of these medications and the optimal doses which should be considered. At the present time, if a man is taking a phytotherapeutic agent and feels that it helps him, I encourage him to stay on it. Men who are taking a phytotherapeutic agent who do not note improvement after 2 to 3 months would probably be best advised to stop it and seek other treatment options for their urinary problems.
Thermotherapy is the primary minimally invasive option available for men with prostatic symptoms who do not want to take long term medication, do not tolerate medication because of side effects, or who have inadequate treatment results with medication. The principle of thermotherapy is that the blood supply to the BPH adenoma (this is what blocks the bladder) is less well developed than the blood supply to the prostate capsule (this is the remainder of the prostate). Given the diminished blood supply, heat applied to the prostate will selectively damage the adenoma without damaging the prostatic capsule. This is the principle by which transurethral needle ablation (TUNA), transurethral microwave therapy (TUMT), the interstitial laser, water induced thermotherapy (WIT) and high intensity focused ultrasound (HIFU) work. Another minimally invasive way to cause therapeutic damage to the BPH adenoma is to sclerose it with ethanol instillation. These options will be discussed in detail below.
Transurethral needle ablation (TUNA) is a highly effective procedure for the relief of LUTS from BPH. A specially designed, small cystoscope is introduced through the urethra. Radiofrequency energy passes into the prostate adenoma through needles in the prostate parenchyma. This energy heats the prostatic tissue in the adenoma to approximately 100-110°C causing the tissue to necrose. The heat also kills the alpha nerves which modulates smooth muscle tone. The result is that the adenomatous tissue contracts and forms scar tissue and a “super alpha blockade” effect is achieved by heat damage to the nerves in the prostate. The result is improvement in urinary symptoms and urinary flow rate with a minimal risk of side effects.
The TUNA procedure can be done using local anesthesia in a urologists office. It can also be done using Lidocaine to “numb” the prostate or using intravenous sedation. Each of these approaches is generally well tolerated. The procedure takes 20 to 45 minutes to perform depending on the size of the patient’s prostate. After the treatment, a small catheter is generally left in the bladder for 2 to 3 days because 20% of patients will have enough swelling in the prostate to block the passage and cause urinary retention. The catheter drainage keeps the bladder empty until the swelling subsides in 2 to 3 days. The risk of impotence and incontinence is extremely low with the TUNA procedure. The risk of retrograde ejaculation in a typical patient would be approximately 3%. In patients with an elevated bladder neck or an enlarged median lobe where the bladder neck area needs to be heated, the risk of retrograde ejaculation is higher, approximately 25-30%.
Transurethral microwave therapy (TUMT) is another treatment option to heat the BPH adenoma. It works on the same principle as the TUNA procedure but the heat is delivered by a different mechanism. With TUMT, a catheter is introduced into the bladder. Toward the end of the catheter there is a microwave antenna which emits microwave energy to heat the BPH adenoma. Depending on the device used, temperatures between 45°C and 80-100°C are achieved. The Prolieve device is one type of microwave catheter which has both a microwave antenna as well as a balloon dilation mechanism for the prostatic urethra. This is a newer TUMT device and combines the long terms benefits of thermotherapy with the short term, transient benefits of balloon dilation. The risk of impotence and incontinence are also very low with TUMT. The risk of retrograde ejaculation is approximately 10%. One potential disadvantage of TUMT is that patients with an elevated bladder neck or an enlarged median lobe cannot be treated with this technology. In addition very small or very large prostates cannot be treated effectively using TUMT. TUMT can be performed using local anesthesia, a prostate block with lidocaine or intravenous sedation as anesthetic options.
Interstitial Laser is a third option to heat the BPH adenoma. With this device, a laser fiber is introduced into the parenchyma of the prostate and energy from the laser is delivered to the tissue to heat it. This accomplishes the same process as TUNA and TUMT in that the BPH adenoma is heated and urinary symptoms and urinary flow are improved. Most urologists who use interstitial laser report that intravenous sedation is required for the best results and patient comfort for this procedure.
Water induced thermotherapy (WIT) uses hot water flowing through a balloon inflated in the prostatic urethra to heat the BPH adenoma. This technology has not achieved results as good as TUNA, TUMT and the interstitial laser and is generally used less than those other technologies.
High intensity focused ultrasound (HIFU) is an investigational treatment that is being evaluated for both BPH and prostate cancer. It is not FDA approved at the present time.
Ethanol ablation is another treatment option which has been described for management of obstructive BPH. This is accomplished by instilling ethanol into the BPH adenoma through a needle introduced into the prostate transurethrally. The ethanol scleroses the BPH tissue which leads to scarring and contraction of the obstructing tissue. This treatment option has not been widely studied and is used less than the other minimally invasive treatment options described above.
Surgical treatment options for prostate enlargement include transurethral resection of the prostate (TURP), laser vaporization of the prostate, transurethral incision of the prostate (TUIP) and open simple prostatectomy.
Transurethral resection of the prostate (TURP) has been used since the 1930’s for treatment of prostate enlargement. The technology for this procedure has improved over the ensuing decades. TURP is still considered the best treatment for improvement in symptoms and urinary flow. However, it is more invasive and carries a greater risk of side effects than medication and minimally invasive options described above.
TURP requires either a general anesthetic or a spinal anesthetic. It is done in a hospital operating room and sometimes requires an overnight stay in the hospital. The obstructing BPH adenoma is removed surgically under direct vision through an endoscope which is placed through the urethra. A wire loop with electro-cautery is used to cut the tissue and to coagulate bleeding after the tissue has been removed. The procedure takes 30 minutes to 1 ½ hours to complete depending on the size of the prostate. TURP gives greater improvement in symptoms, urinary flow and bladder emptying than medication or any other minimally invasive options.
There is approximately a 1% risk of urinary incontinence, a 10% risk of erectile impotence, a 70% risk of retrograde ejaculation and a 3% risk of a urethral stricture or bladder neck contracture after TURP.
Laser vaporization of the prostate is a procedure which accomplishes the same end result as a TURP but uses laser energy instead of electro-cautery to vaporize away the obstructing BPH adenoma. The advantage of the laser over TURP is that there is less bleeding and a lower risk of impotence. The risk of incontinence and ejaculatory dysfunction is similar. The laser is also generally done with general anesthesia or a spinal anesthetic but can be consistently performed as same day surgery with the patient going home without a catheter in the majority of cases. The procedure takes slightly longer to perform than a TURP but the advantage of minimal bleeding and a shorter hospital stay counteracts this potential disadvantage.
Transurethral incision the prostate (TUIP) is an option used for men with relatively small prostates who have an elevated bladder neck causing bladder outlet obstruction. This procedure also requires a general or spinal anesthetic and is done in a hospital operating room. Bleeding is generally minimal. The risk of incontinence and impotence is similar to that with TURP. The risk of retrograde ejaculation with TUIP is 40-50%. This procedure, in properly chosen patients, gives treatment results similar to that seen with TURP.
Open simple prostatectomy is used for men with exceptionally large prostates where a transurethral approach is not feasible because of the large prostate size. This procedure requires a general or spinal anesthetic and often 2 to 3 days of hospitalization. An incision is made in the lower abdomen, and the adenoma is surgically dissected and removed from the prostatic fossa. Bleeding can be heavy from this procedure and blood transfusion is sometimes required. The risk of incontinence is 1-2%, impotence approximately 10%, retrograde ejaculation 90% and bladder neck contracture 3%. An open simple prostatectomy gives symptom improvement that is even better than that seen after TURP. It is obviously a more invasive treatment approach.
Re-treatment can be required after any of the therapeutic options discussed in this article. The re-treatment rate is lowest after open simple prostatectomy. The re-treatment rate after TURP has been estimated to be approximately 2% per year. Re-treatment rates after the minimally invasive options are variable depending on how the re-treatment is defined. Some studies quantify surgical re-treatment whereas others consider the need for medication to be a case requiring re-treatment. In any event, the re-treatment rates after minimally invasive options are higher than those after TURP.
If a patient goes on medication and results are inadequate or non-durable, it is relatively simple to take the next step and consider a minimally invasive option or surgery. Given the minimum morbidity of minimally invasive treatment options, re-treatment with another minimally invasive procedure or with surgery does not represent a major hurdle for the majority of patients.
BPH is a common disease process in men as they age. The exact mechanism of the disease is not clear but male hormones and advancing age are required for prostate enlargement to occur. Some men can be managed with watchful waiting while others require treatment. Treatment options range from medications to minimally invasive treatment options to surgical correction of the prostatic obstruction.
Men with urinary symptoms should consult their physician for an evaluation to determine the cause of the problem and to determine whether treatment is necessary. Fortunately, because of advancing technology with medications and treatment devices, men have a wide range of options to choose from when they require treatment for symptomatic BPH.