Health and Prostate

α-Adrenergic blockers

It has been suggested that the dynamic component of obstruction, smooth muscle tone in bladder heck, prostate, urethra, and prostatic capsule, is responsible for the variation in symptoms. Prostatic smooth muscle tone is regulated by the autonomic nervous system. The contractile response of prostatic tissue to norepinephrine and its abolishment by pretreatment with OC-adrenergic antagonists was first demonstrated by Gaine and colleagues during the 1970s. α1 and α2-receptors have recently been identified in human prostate and bladder neck by radioligand receptor studies. Contractile response is predominantly mediated by α1-receptors.

Well-controlled studies have been performed demonstrating the efficacy of phe-noxybenzamine (non-selective α-adrenergic antagonist), prazosin (α1-adrenergic antagonist), and terazosin (α1-adrenergic antagonist) in the treatment of Benign Prostatic Hyperplasia. Meaningful improvements in symptom score, global assessment, and urodynamic parameters (peak flow rate, mean flow rate) have been documented with these agents. Side effects have been minimal, and hypotension was not a problem.

α -Adrenergic blockade can be expected to provide a degree of relief from outlet obstruction. Once long-term experience with these agents has been gained, their role in the management of Benign Prostatic Hyperplasia can be clarified.

Anticholinergic agents

A literature review of the medical management of Benign Prostatic Hyperplasia is remarkable for the fact that the anticholinergic agents are virtually ignored. Approximately 75% of patients with BPH have significant irritative symptoms, such as frequency, urgency, and nocturia, which are considered to be due to detrusor hypertrophy. In many of these patients, the obstructive symptoms (Table 3) are minor and of little concern. The efficacy of such medications as oxybutynin (Ditropan) in the treatment of unstable bladders is clear. It could be that these medications are not used more often for fear of causing urinary retention.

Of the 75% of patients with irritative symptoms, 33% will have persistent symptoms after relief of outlet obstruction. It is useful to know whether these symptoms can be medically controlled. If they cannot, then the patient may have little benefit, symptomatically, from a transurethral prostatic resection (TUPR) and should be aware of this before the operation.

There are many causes for irritative voiding symptoms. The physician should rule out infection. If gross or microscopic hematuria is present, then bladder cancer must be ruled out. If the patient is adequately emptying his bladder, as determined by palpation, ultrasound, or postvoid catheterization, then a trial of anticholinergic medication, such as oxybutynin, 2.5 mg by mouth, is worthwhile. A significant number of patients benefit substantially; moreover the drug can occasionally be tapered and discontinued after 3 to 6 months without a return of symptoms. If outlet obstruction worsens, then one can proceed to prostatectomy, secure in the knowledge that any persisting irritative symptoms can be controlled after surgery.

Benign Prostatic Hyperplasia (BPH) is the most common neoplasm affecting humans. More than 400 000 prostatectomies are performed annually in the United States, second only to cataract extractions in charges to Medicare.

In an era of limited health care funds, the indications for and efficacy of traditional therapy must be reviewed. A variety of new therapies for BPH are being clinically evaluated. Any new treatment will need to show comparable efficacy, safety, and cost efficiency.

Natural history

Histologically detectable Benign Prostatic Hyperplasia has an increasing incidence with age, with virtually all men demonstrating hyperplasia by age 80. However, clinical enlargement is detected in only 50%. Of these, roughly half will develop symptoms sufficient to seek treatment. It is estimated that a 50-year-old man has a 10% to 20% chance of receiving surgery for relief of bladder outlet obstruction in his lifetime.

The symptoms of bladder outlet obstruction vary significantly over time. It has been proposed that oudet obstruction has both a static and dynamic component. Mechanical occlusion of the urethral lumen by the enlarging gland is the static component, while smooth muscle tone within the urethra, prostate, prostatic capsule, and bladder neck is the dynamic element.

The clinical course in patients with moderate symptoms is unpredictable. Several investigators have looked at long-term follow up in these patients. Ball and colleagues followed 107 patients for a minimum of 3 years. Ten required surgery, leaving 97 for evaluation by subjective and objective criteria. Subjectively, 24% were worse, 29% were better, and 47% reported no change. Objectively, urodynamic parameters were assessed: 49% deteriorated, 28% improved, and 23% remained stable.

There was significant overlap between the groups, indicating a poor correlation between subjective and objective criteria. Other studies support this lack of agreement between symptomatic outcome and urodynamic parameters in Benign Prostatic Hyperplasia.

The accepted objective indications for prostatectomy include acute retention azo-temia secondary to outlet obstruction and recurrent urinary tract infection related to chronic residual urine. However, fewer than 20% of prostatectomies are carried out on the basis of objective criteria; the rest are performed for symptomatic improvement. Therefore, the assessment of symptoms and subjective response to therapy is essential in treatment decisions and evaluation of therapeutic intervention.

Hormonal therapy

The prostate is an aggregation of tubuloalveolar glands, supported by an unusually dense fibromuscular stroma. The stroma is made up of fibroblasts, smooth muscle cells, and collagen. Benign prostatic hyperplasia is the result of proliferation of glandular epithelium and fibromuscular stroma. In a morphologic study, Bartsch and colleagues determined that Benign Prostatic Hyperplasia results primarily from an increase in stroma, as the normal stroma to epithelium ratio increases from 2:1 to 5:1.

The development of BPH requires aging and the presence of androgens. Elimination of androgens, either medically or surgically, will result in decreased protein synthesis, in tissue involution, and in cell death in the prostate. Huggins and Stevens demonstrated involution of the prostatic epithelium with little effect on the stroma in men with BPH after castration. Similarly, Peters and Walsh reported a reduction of 40% in epithelial volume and 20% in stroma in nine patients treated with the luteinizing hormone-releasing hormone agonist nafarelin acetate. As BPH appears to be primarily a disease of the stroma, one would expect androgen ablation to have a limited role.

Nevertheless, a variety of agents inducing androgen withdrawal have been studied (Table 1). There are valid methodologic concerns with these studies; however, several trends are evident. All have been shown to reduce size by 30% to 40% over 3 to 6 months. This reduction is reversible within 6 months of stopping the agent. The stromal portion is responsible for incompleteness of shrinkage, as biopsies reveal the response is primarily epithelial. Unfortunately, no trial assessed subjective outcome using a standardized symptom score, and most did not use placebo controls. The mean improvement in peak urinary flow rate was approximately 33%. These urodynamic changes were clinically significant.

These agents clearly reduce gland size, but they do not create a functionally unobstructed state. They are also limited by side effects of impotence and hot flushes. As their effect is reversible, continuous therapy is needed. Given present life expectancies, this represents an enormous potential cost (Table 2).

Questions and Answers

1. Have similar studies been done comparing drug treatment to surgery or watchful waiting?

No. It’s very unlikely that anyone could get funding for such a study. It’s pretty clear that surgery is much more effective than medication.

2. Can watchful waiting really be considered a treatment that can succeed or fail?

Yes, there’s a huge amount of improvement that occurs in watchful waiting over time, particularly if they do the behavioural approaches you described – avoid medications that make it worse, stay away from caffeine and alcohol, don’t drink fluids in the evening and empty the bladder before going to bed. These things seem to have a significant effect on a lot of men. Also, benign prostatic hyperplasia symptoms come and go naturally – you see that even with placebo, things just get better. If you’re not really badly bothered, watchful waiting and drugs are reasonable alternatives, but if you’re badly bothered, you’re probably wasting your time with these options.

3. Does the age of the patient make watchful waiting more or less appropriate?

Ironically, it’s in the younger patients that more thought should be given about drug treatment, because they have so much more time to pile up the costs and side effects. If you’re young and choose medication, you have to understand that you’re potentially going to be on them for the rest of your life. The price of the drugs will surpass that of surgery after a few years, and you still don’t know if you’ll eventually need surgery anyway. I always recommend that, if a young man is going to start on the drugs, he do so for two or three months, then stop for a couple of months and see if it makes any difference, because so many men will get better anyhow – it may be no better than a sugar pill. They should stop and start a few times before deciding to commit themselves to lifelong drug therapy, to make sure it’s working. For an older man with a more limited life expectancy, he has less time to benefit from surgery and more risk for complications. Therefore, drugs may actually make more sense in an older man. This is the opposite of what’s going on in most practices.

4. Can you explain the discrepancy between the men’s evaluation of sexual performance and that of their partners?

The real point is that neither surgery nor watchful waiting differed in their effect on potency. If you looked at those men who were actually impotent, their spouses were more likely to agree. But it’s not unusual for the man and the wife to have different perceptions of sexual function. The disagreement wasn’t significant.

Editorial Commentary

This is the only study that’s ever looked at TURP, which is a very common surgery, and compared it to watchful waiting. We looked at people for at least three years and up to six years. The study shows that, particularly for men who are bothered, surgery is likely to be very beneficial and not likely to result in impotence or incontinence. Prior to this, all the studies showing that surgery results in impotence were not controlled. Many older men become impotent anyway, and then blame the surgery – you always want to look back and blame something. In this study, we looked at that very carefully and found no evidence that it’s true.

The urinary symptoms of benign prostatic hyperplasia (BPH) can range from very mild to severe enough to require prompt surgical treatment. Men with moderate symptoms of BPH do not face immediate health risks, but are typically bothered by symptoms such as frequent urination, dribbling and a hesitant urinary stream. These men are presented with the options of drug therapy, surgery to reduce the volume of the prostate, or watchful waiting, which monitors symptoms and employs behavioural measures, like learning to relax the muscles while urinating and eliminating caffeine and alcohol, to avoid or delay surgery. This study set out to compare the effectiveness of surgery and watchful waiting in managing moderate symptoms of BPH.

Between 1986 and 1989, 556 men age 55 or older were recruited into the study at participating U.S. veterans’ medical centres. All had moderate urinary symptoms of benign prostatic hyperplasia, making them appropriate candidates for either watchful waiting or surgery. After obtaining the consent of participants and conducting baseline exams, the researchers randomly assigned patients to either surgery, consisting of transurethral resection of the prostate (TURP), or watchful waiting, with consideration given to the severity of symptoms and the hospital in which care would be administered. Those assigned to surgery underwent the operation within two weeks. The men were seen by a general practitioner six to eight weeks after the beginning of the study, and then twice a year for three years.

The effectiveness of treatment was judged in two ways. The first was according to the number of treatment failures in each group. Failure was defined as any of the following: death, persistent urinary retention, residual urine (the amount left in the bladder after urinating) of over 350 ml, incontinence requiring the use of pads or other devices, a doubling of the serum creatinine level (a measure of kidney function) over the course of the study, or symptom scores over 23 at one visit or over 20 at two visits in a row.

Treatments were also judged according to changes in the urinary symptoms men experienced and in how much these bothered them. Peak urinary flow and residual urine were measured at each follow-up visit. Questionnaires were completed at the start, at one year and at the end of the study to provide a score representing how much benign prostatic hyperplasia symptoms interfered with daily life, sexual function and overall well-being.

Complications from prostate surgery were rare, and 78% of men were out of hospital four days after surgery. Ten percent of men who had surgery were diagnosed with prostate cancer after tests were done on the tissue that had been removed. Mortality rates over the three years were similar in the surgery and watchful waiting groups. As well, perceived changes in sexual performance were similar for the two groups, with 19% of the surgery group and 21% of the watchful waiting group reporting a worsening of sexual performance over the three years, with 3% in each group reporting an improvement. However, most of the spouses thought that the men’s sexual performance had been unaffected by either treatment.

Incontinence symptoms, defined as dripping urine or wetting their pants, were improved much more by surgery than by watchful waiting. At the start of the study, 22% of surgery patients and 18% of watchful waiting patients had reported moderate to severe incontinence. After three years, only 5.7% of the surgery group, but 12% of the others, were still bothered by this problem. In other words, among the men who had initially complained of them, these symptoms were reduced or eliminated in one-third of watchful waiting patients, but in about three-quarters of the surgery patients.

Treatment failures were more than twice as frequent in the watchful waiting group as in the surgery group (6.1 per 100 person-years as opposed to 3.0). Three problems accounted for most of the failures in the watchful waiting group: persistent urinary retention, high residual urine volumes and high symptom scores. Twenty men initially assigned to the watchful waiting group had surgery within the three years because of treatment failure.

This study found surgery to be more effective than watchful waiting for men with moderate benign prostatic hyperplasia symptoms. Men who reported being substantially bothered by urinary symptoms at the start appeared to benefit most from surgery. Ninety-one percent of the men who received surgery saw improvement in their symptoms, as opposed to 62% of those on watchful waiting. Men with very bothersome symptoms were likely to switch from watchful waiting to surgery within the three-year follow-up period. The authors conclude that, while men who are only mildly bothered by urinary symptoms of BPH may safely choose watchful waiting, men whose symptoms substantially reduce quality of life have the most to gain from TURP. A good number of those who choose watchful waiting are really only delaying surgery, rather than averting the need for it altogether.